A Comparison of In Vitro Points of Departure with Human Blood Levels for Per- and Polyfluoroalkyl Substances (PFAS).

Per- and polyfluoroalkyl substances (PFAS) are widely used, and their fluorinated state contributes to unique uses and stability but also long half-lives in the environment and humans. PFAS have been shown to be toxic, leading to immunosuppression, cancer, and other adverse health outcomes. Only a small fraction of the PFAS in commerce have been evaluated for toxicity using in vivo tests, which leads to a need to prioritize which compounds to examine further. Here, we demonstrate a prioritization approach that combines human biomonitoring data (blood concentrations) with bioactivity data (concentrations at which bioactivity is observed in vitro) for 31 PFAS. The in vitro data are taken from a battery of cell-based assays, mostly run on human cells. The result is a Bioactive Concentration to Blood Concentration Ratio (BCBCR), similar to a margin of exposure (MoE). Chemicals with low BCBCR values could then be prioritized for further risk assessment. Using this method, two of the PFAS, PFOA (Perfluorooctanoic Acid) and PFOS (Perfluorooctane Sulfonic Acid), have BCBCR values < 1 for some populations. An additional 9 PFAS have BCBCR values < 100 for some populations. This study shows a promising approach to screening level risk assessments of compounds such as PFAS that are long-lived in humans and other species.

Characterizing Chemical Exposure Trends from NHANES Urinary Biomonitoring Data.

BACKGROUND: Xenobiotic metabolites are widely present in human urine and can indicate recent exposure to environmental chemicals. Proper inference of which chemicals contribute to these metabolites can inform human exposure and risk. Furthermore, longitudinal biomonitoring studies provide insight into how chemical exposures change over time. OBJECTIVES: We constructed an exposure landscape for as many human-exposure relevant chemicals over as large a time span as possible to characterize exposure trends across demographic groups and chemical types. METHODS: We analyzed urine data of nine 2-y cohorts (1999-2016) from the National Health and Nutrition Examination Survey (NHANES). Chemical daily intake rates (in milligrams per kilogram bodyweight per day) were inferred, using the R package bayesmarker, from metabolite concentrations in each cohort individually to identify exposure trends. Trends for metabolites and parents were clustered to find chemicals with similar exposure patterns. Exposure variation by age, gender, and body mass index were also assessed. RESULTS: Intake rates for 179 parent chemicals were inferred from 151 metabolites (96 measured in five or more cohorts). Seventeen metabolites and 44 parent chemicals exhibited fold-changes ≥10 between any two cohorts (deltamethrin, di-n-octyl phthalate, and di-isononyl phthalate had the greatest exposure increases). Di-2-ethylhexyl phthalate intake began decreasing in 2007, whereas both di-isobutyl and di-isononyl phthalate began increasing shortly before. Intake for four parabens was markedly higher in females, especially reproductive-age females, compared with males and children. Cadmium and arsenobetaine exhibited higher exposure for individuals >65 years of age and lower for individuals <20 years of age. DISCUSSION: With appropriate analysis, NHANES indicates trends in chemical exposures over the past two decades. Decreases in exposure are observable as the result of regulatory action, with some being accompanied by increases in replacement chemicals. Age- and gender-specific variations in exposure were observed for multiple chemicals. Continued estimation of demographic-specific exposures is needed to both monitor and identify potential vulnerable populations. https://doi.org/10.1289/EHP12188.

Suspect Screening Analysis of Pooled Human Serum Samples Using GC × GC/TOF-MS.

Humans interact with thousands of chemicals. This study aims to identify substances of emerging concern and in need of human health risk evaluations. Sixteen pooled human serum samples were constructed from 25 individual samples each from the National Institute of Environmental Health Sciences' Clinical Research Unit. Samples were analyzed using gas chromatography (GC) × GC/time-of-flight (TOF)-mass spectrometry (MS) in a suspect screening analysis, with follow-up confirmation analysis of 19 substances. A standard reference material blood sample was also analyzed through the confirmation process for comparison. The pools were stratified by sex (female and male) and by age (≤45 and >45). Publicly available information on potential exposure sources was aggregated to annotate presence in serum as either endogenous, food/nutrient, drug, commerce, or contaminant. Of the 544 unique substances tentatively identified by spectral matching, 472 were identified in females, while only 271 were identified in males. Surprisingly, 273 of the identified substances were found only in females. It is known that behavior and near-field environments can drive exposures, and this work demonstrates the existence of exposure sources uniquely relevant to females.

Cutting-edge computational chemical exposure research at the U.S. Environmental Protection Agency.

Exposure science is evolving from its traditional "after the fact" and "one chemical at a time" approach to forecasting chemical exposures rapidly enough to keep pace with the constantly expanding landscape of chemicals and exposures. In this article, we provide an overview of the approaches, accomplishments, and plans for advancing computational exposure science within the U.S. Environmental Protection Agency's Office of Research and Development (EPA/ORD). First, to characterize the universe of chemicals in commerce and the environment, a carefully curated, web-accessible chemical resource has been created. This DSSTox database unambiguously identifies >1.2 million unique substances reflecting potential environmental and human exposures and includes computationally accessible links to each compound's corresponding data resources. Next, EPA is developing, applying, and evaluating predictive exposure models. These models increasingly rely on data, computational tools like quantitative structure activity relationship (QSAR) models, and machine learning/artificial intelligence to provide timely and efficient prediction of chemical exposure (and associated uncertainty) for thousands of chemicals at a time. Integral to this modeling effort, EPA is developing data resources across the exposure continuum that includes application of high-resolution mass spectrometry (HRMS) non-targeted analysis (NTA) methods providing measurement capability at scale with the number of chemicals in commerce. These research efforts are integrated and well-tailored to support population exposure assessment to prioritize chemicals for exposure as a critical input to risk management. In addition, the exposure forecasts will allow a wide variety of stakeholders to explore sustainable initiatives like green chemistry to achieve economic, social, and environmental prosperity and protection of future generations.

A Machine Learning Model to Estimate Toxicokinetic Half-Lives of Per- and Polyfluoro-Alkyl Substances (PFAS) in Multiple Species.

Per- and polyfluoroalkyl substances (PFAS) are a diverse group of man-made chemicals that are commonly found in body tissues. The toxicokinetics of most PFAS are currently uncharacterized, but long half-lives (t½) have been observed in some cases. Knowledge of chemical-specific t½ is necessary for exposure reconstruction and extrapolation from toxicological studies. We used an ensemble machine learning method, random forest, to model the existing in vivo measured t½ across four species (human, monkey, rat, mouse) and eleven PFAS. Mechanistically motivated descriptors were examined, including two types of surrogates for renal transporters: (1) physiological descriptors, including kidney geometry, for renal transporter expression and (2) structural similarity of defluorinated PFAS to endogenous chemicals for transporter affinity. We developed a classification model for t½ (Bin 1: <12 h; Bin 2: <1 week; Bin 3: <2 months; Bin 4: >2 months). The model had an accuracy of 86.1% in contrast to 32.2% for a y-randomized null model. A total of 3890 compounds were within domain of the model, and t½ was predicted using the bin medians: 4.9 h, 2.2 days, 33 days, and 3.3 years. For human t½, 56% of PFAS were classified in Bin 4, 7% were classified in Bin 3, and 37% were classified in Bin 2. This model synthesizes the limited available data to allow tentative extrapolation and prioritization.

Characterizing surface water concentrations of hundreds of organic chemicals in United States for environmental risk prioritization.

BACKGROUND: Thousands of chemicals are observed in freshwater, typically at trace levels. Measurements are collected for different purposes, so sample characteristics vary. Due to inconsistent data availability for exposure and hazard, it is complex to prioritize which chemicals may pose risks. OBJECTIVE: We evaluated the influence of data curation and statistical practices aggregating surface water measurements of organic chemicals into exposure distributions intended for prioritizing based on nation-scale potential risk. METHODS: The Water Quality Portal includes millions of observations describing over 1700 chemicals in 93% of hydrologic subbasins across the United States. After filtering to maintain quality and applicability while including all possible samples, we compared concentrations across sample types. We evaluated statistical methods to estimate per-chemical distributions for chosen samples. Overlaps between resulting exposure ranges and distributions representing no-effect concentrations for multiple freshwater species were used to rank estimated chemical risks for further assessment. RESULTS: When we apply explicit data quality and statistical assumptions, we find that there are 186 organic chemicals for which we can make screening-level estimates of surface water chemical concentration. Of the original 1700 observed chemicals, this number decreased primarily due to a predominance of censored values (that is, observations indicating concentrations too low to be measured). We further identify 423 chemicals where all measurements were censored but, through consideration of detection limits, risk might still be prioritized based on the detection limits themselves. In the final set of 1.5 million samples, the median environmental concentration of one chemical (acetic acid) exceeded the 5th percentile of no-effect concentrations for the most delicate freshwater species (the highest priority risk condition identified here), and a further 29 chemicals were identified for possible further evaluation based on a small margin between occurrence and toxicity values. SIGNIFICANCE: This method shows the broad range of chemical concentrations seen for organic chemicals across the country and identifies methods of determining their central tendency, allowing for researchers to characterize higher-than-normal or lower-than-normal surface water conditions as well as providing an overall indication of the presence of organic chemicals in the United States. The highest chemical concentrations did not always indicate the highest-risk conditions. Even when accounting for the high level of uncertainty in these data due to differences in data collection and reporting across the set, some chemicals may still be categorized as higher environmental risk than others using this method, providing value to chemical safety decision makers and researchers by suggesting avenues for more focused investigation.

Bayesian inference of chemical exposures from NHANES urine biomonitoring data.

BACKGROUND: Knowing which environmental chemicals contribute to metabolites observed in humans is necessary for meaningful estimates of exposure and risk from biomonitoring data. OBJECTIVE: Employ a modeling approach that combines biomonitoring data with chemical metabolism information to produce chemical exposure intake rate estimates with well-quantified uncertainty. METHODS: Bayesian methodology was used to infer ranges of exposure for parent chemicals of biomarkers measured in urine samples from the U.S population by the National Health and Nutrition Examination Survey (NHANES). Metabolites were probabilistically linked to parent chemicals using the NHANES reports and text mining of PubMed abstracts. RESULTS: Chemical exposures were estimated for various population groups and translated to risk-based prioritization using toxicokinetic (TK) modeling and experimental data. Exposure estimates were investigated more closely for children aged 3 to 5 years, a population group that debuted with the 2015-2016 NHANES cohort. SIGNIFICANCE: The methods described here have been compiled into an R package, bayesmarker, and made publicly available on GitHub. These inferred exposures, when coupled with predicted toxic doses via high throughput TK, can help aid in the identification of public health priority chemicals via risk-based bioactivity-to-exposure ratios.

A Systematic Review of Published Physiologically-based Kinetic Models and an Assessment of their Chemical Space Coverage.

Across multiple sectors, including food, cosmetics and pharmaceutical industries, there is a need to predict the potential effects of xenobiotics. These effects are determined by the intrinsic ability of the substance, or its derivatives, to interact with the biological system, and its concentration-time profile at the target site. Physiologically-based kinetic (PBK) models can predict organ-level concentration-time profiles, however, the models are time and resource intensive to generate de novo. Read-across is an approach used to reduce or replace animal testing, wherein information from a data-rich chemical is used to make predictions for a data-poor chemical. The recent increase in published PBK models presents the opportunity to use a read-across approach for PBK modelling, that is, to use PBK model information from one chemical to inform the development or evaluation of a PBK model for a similar chemical. Essential to this process, is identifying the chemicals for which a PBK model already exists. Herein, the results of a systematic review of existing PBK models, compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) format, are presented. Model information, including species, sex, life-stage, route of administration, software platform used and the availability of model equations, was captured for 7541 PBK models. Chemical information (identifiers and physico-chemical properties) has also been recorded for 1150 unique chemicals associated with these models. This PBK model data set has been made readily accessible, as a Microsoft Excel® spreadsheet, providing a valuable resource for those developing, using or evaluating PBK models in industry, academia and the regulatory sectors.

Correction: Development and evaluation of a high throughput inhalation model for organic chemicals.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Development and evaluation of a high throughput inhalation model for organic chemicals.

Currently it is difficult to prospectively estimate human toxicokinetics (particularly for novel chemicals) in a high-throughput manner. The R software package httk has been developed, in part, to address this deficiency, and the aim of this investigation was to develop a generalized inhalation model for httk. The structure of the inhalation model was developed from two previously published physiologically based models from Jongeneelen and Berge (Ann Occup Hyg 55:841-864, 2011) and Clewell et al. (Toxicol Sci 63:160-172, 2001), while calculated physicochemical data was obtained from EPA's CompTox Chemicals Dashboard. In total, 142 exposure scenarios across 41 volatile organic chemicals were modeled and compared to published data. The slope of the regression line of best fit between log-transformed simulated and observed blood and exhaled breath concentrations was 0.46 with an r2 = 0.45 and a root mean square error (RMSE) of direct comparison between the log-transformed simulated and observed values of 1.11. Approximately 5.1% (n = 108) of the data points analyzed were >2 orders of magnitude different than expected. The volatile organic chemicals examined in this investigation represent small, generally lipophilic molecules. Ultimately this paper details a generalized inhalation component that integrates with the httk physiologically based toxicokinetic model to provide high-throughput estimates of inhalation chemical exposures.

Database of pharmacokinetic time-series data and parameters for 144 environmental chemicals.

Time courses of compound concentrations in plasma are used in chemical safety analysis to evaluate the relationship between external administered doses and internal tissue exposures. This type of experimental data is rarely available for the thousands of non-pharmaceutical chemicals to which people may potentially be unknowingly exposed but is necessary to properly assess the risk of such exposures. In vitro assays and in silico models are often used to craft an understanding of a chemical's pharmacokinetics; however, the certainty of the quantitative application of these estimates for chemical safety evaluations cannot be determined without in vivo data for external validation. To address this need, we present a public database of chemical time-series concentration data from 567 studies in humans or test animals for 144 environmentally-relevant chemicals and their metabolites (187 analytes total). All major administration routes are incorporated, with concentrations measured in blood/plasma, tissues, and excreta. We also include calculated pharmacokinetic parameters for some studies, and a bibliography of additional source documents to support future extraction of time-series. In addition to pharmacokinetic model calibration and validation, these data may be used for analyses of differential chemical distribution across chemicals, species, doses, or routes, and for meta-analyses on pharmacokinetic studies.